Annex 4. GRADE evidence-to-decision tables

Older terminology used in the context of TB preventive treatment (TPT), such as latent TB infection (LTBI) and active TB, has been retained in the original text of the tables.

PICO 1: What is the prevalence of TB infection, risk of progression to TB disease and cumulative prevalence of TB disease among household contacts without HIV in different age groups in high TB incidence countries?

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Assessment

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Summary of judgements

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Conclusions

What is the prevalence of TB infection, risk of progression to TB disease and cumulative prevalence of TB disease among household contacts without HIV in different age groups in high TB incidence countries?

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GRADE tables: SR1

SR1. Risk for TB infection among household contacts by age stratum: high TB incidence countries

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a Potential selection bias in (4), as only 69% of participants were household contacts. 
b Potential misclassification: Eight studies (5–6,9,12,13,15,16) did not indicate whether household contacts with active TB were excluded from the analysis or did not provide sufficient data for calculation of the number of household contacts with active TB per age stratum. 
c High heterogeneity among studies (I2 = 94%), probably due to differences in background TB incidence. The risk ratios of two studies (3,7) showed opposite effects. 
d Small sample size in (7) (n < 50). 
e Potential misclassification: Reports of seven studies (5,7,9,12,13,15,16) did not indicate whether household contacts with active TB were excluded from the analysis or did not provide sufficient data for calculation of the number of household contacts with active TB per age stratum. 
f High heterogeneity among studies (I2 = 97%) probably due to differences in background TB incidence. The risk ratio in one study (7) showed the opposite effect. 
g Wide 95% CI of pooled risk ratio. Small sample size in (7) (n < 50) and (13) (n < 100). 
h Studies included: (5,7,10,12,14,17–27). 
i Potential selection bias in (18), as only 89% of participants were household contacts.
j High heterogeneity among studies (I2 = 93%), probably due to differences in background TB incidence. The risk ratios in three studies (7,20,22) showed opposite effects.
k Small sample size in (7) and (19) (n < 50). 
l Studies included: (5–7,10–12,14–17,20–28). 
m Potential misclassification: The reports of ten studies (5–7,12,13,16,21,22,25,28) did not indicate whether household contacts with active TB were excluded from the analysis or did not provide sufficient data for calculation of the number of household contacts with active TB per age stratum. 
n High heterogeneity among studies (I2 = 98%), probably due to differences in background TB incidence. 
o Small sample size in 7 and 28 (n < 100).

 

SR2

SR2. Development of active TB disease in household contacts with TB infection in high TB incidence countries

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Because there were few studies in the other categories, only data from studies in high TB incidence countries with a follow-up of 1–2 years are presented in the table.
a Serious inconsistencies due to heterogeneity (I2 = 71%). One study showed an increased risk in the age group 5–15 years. This was not observed in the other studies.
b Few events.
c High heterogeneity among studies (I2 = 89.3%), probably due to differences in background TB incidence and methods used for diagnosis of active TB.

 

SR3

SR3. Cumulative prevalence of TB disease in household contacts, irrespective of baseline TB infection status, in high TB incidence countries

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Because there were few studies in the other categories, only data from studies in high TB incidence countries with a follow-up of 1–2 years are presented in the table.

a One outlier study (29) was excluded because of uncertainty about the cases that were included (co-prevalent vs incident cases). 
b High heterogeneity among studies (I2 = 87.6%), probably due to differences in background TB incidence.

 

Comparison with the general population for SR2

Development of TB disease in household contacts with TB infection in high TB incidence countries 
Comparison with the general population (follow-up, 12 months)

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a LTBI does not apply to the general population. 
b Ascertainment bias highly likely. TB cases in the general population detected passively, while TB cases in the contacts detected actively; therefore, relative and absolute risks might be overestimated. The composition of the general and the study populations differs (general population of all ages versus a specific age group). 
c High heterogeneity (I2 = 83.9%) among studies, probably due to differences in background TB incidence. 
d Serious imprecision with a wide 95% CI for the effect estimates, probably due to the small study size and number of outcome events. 
e I2 = 72.5%, indicating moderate heterogeneity, probably due to differences in background TB prevalence; however, there is a trend across age groups and studies. 
f Few events and wide 95% CI.

Development of TB disease in household contacts with TB infection in high TB incidence countries Comparison with the general population (follow-up ≤ 24 months)a

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a These comparisons are based on studies with a maximum follow-up of 24 months. The TB incidence in the general population was multiplied by a factor of 2 to estimate the number of cases occurring over 24 months. 
b LTBI does not apply to the general population. 
c Ascertainment bias highly likely, because TB cases in the general population detected passively, while TB cases in the contacts detected actively. As a result, the relative and absolute risks might be overestimated. The composition of the general and study populations differs (general population of all ages versus a specific age group). The TB incidence in the population was estimated by multiplying the annual notification rate by a factor of 2. 
d High heterogeneity among studies (I2 = 84.4%), probably due to differences in background TB incidence. 
e Few events and wide 95% CI. 
f I2 = 88.1%, indicating high heterogeneity, probably due to differences in background TB prevalence; however, there is a trend across age groups and studies. 
g I2 = 16%.

 

Comparison with the general population for SR3

Cumulative prevalence of TB in household contacts, irrespective of baseline TB infection status, in high TB incidence countries Comparison with the general population (follow-up of 12 months) 

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a Ascertainment bias highly likely, because TB cases in the general population detected passively, while TB cases in the contacts detected actively. As a result, the relative and absolute risks might be overestimated. The composition of the general and study populations differs (general population of all ages versus a specific age group).

b I2 = 0%.

c Few events and wide 95% CI.

 

Cumulative prevalence of TB disease in household contacts, irrespective of baseline TB infection status, in high TB incidence countries Comparison with the general population (follow-up of 24 months)a

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a These comparisons were made in studies with a maximum follow-up of 24 months. The TB incidence in the general population was multiplied by a factor of 2 to estimate the number of cases occurring during 24 months.

b Ascertainment bias highly likely, because TB cases in the general population detected passively, while TB cases in the contacts detected actively. As a result, the relative and absolute risks might be overestimated. The composition of the general and study populations differs (general population of all ages versus a specific age group), and the TB incidence in the population was estimated by multiplying the yearly notification rate by a factor of 2.

c Moderate heterogeneity among studies (I2 = 67.1%), probably due to differences in background TB incidence.

d Few events and wide 95% CI.

e High heterogeneity among studies (I2 = 87.5%), probably due to differences in background TB incidence.

f Moderate heterogeneity among studies (I2 = 72.5%), probably due to differences in background TB incidence.

 

PICO 2: What is the accuracy of WHO symptomatic screening to exclude TB disease in individuals with HIV on antiretroviral treatment (ART)?

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Assessment

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Summary of judgements

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Conclusions

What is the accuracy of WHO symptomatic screening plus abnormal chest radiography for excluding TB disease in individuals with HIV on antiretroviral treatment (ART)?

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GRADE tables

Question: What is the performance of WHO-recommended four-symptom screening to exclude TB disease in individuals with HIV?

Population: Adults and adolescents with HIV on ART
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From references 31–37

a Significant heterogeneity for sensitivity and specificity. Downgraded by 1.

b Wide confidence intervals. Downgraded by 1.

c Possibility of publication bias not excluded, but not considered of sufficient concern to downgrade.

 

Question: What is the performance of combination of CXR and WHO-recommended four-symptom screening to exclude TB disease in individuals with HIV?

Population: Adults and adolescents with HIV on ART
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From references 31 and 36 

a Imprecise estimate for sensitivity; downgraded by 1. 

b Possibility of publication bias not excluded but not considered of sufficient concern to downgrade.

 

PICO 3: What is the accuracy of symptomatic screening and/or CXR to exclude TB disease in contacts of people with pulmonary TB without HIV in high TB incidence countries?

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Assessment

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Summary of judgements

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Conclusions

What is the accuracy of symptomatic screening and/or CXR to exclude TB disease in contacts of people with pulmonary TB without HIV in high TB incidence countries?

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GRADE tables

Question: What is the accuracy of symptomatic screening and/or chest x-ray to exclude TB disease in contacts of people with pulmonary TB without HIV in high TB incidence countries?

Index test: any abnormality in CXR| Reference test: Sputum culture and/or smear
Place of testing: Triage
Test–treatment pathway: CXR positive ➞ confirmatory test (mycobacterial culture or GeneXpert) ➞ anti-TB chemotherapy (6–9 months of antibiotics)
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Studies included: references 38,42,45,47–50 

a Limitations in study design (see QUADAS-2): High risk of selection bias in one study (38). In all studies, less than half the participants received the reference standard; accuracy was calculated under the assumption that those who did not receive the reference standard were culture- and/or smear-negative (no active TB). 

b Indirectness (see QUADAS-2): Some concern about applicability of reference standard in two studies. No downgrading. 

c Inconsistency: Little heterogeneity in sensitivity or specificity (from visual inspection of 95% CIs). 

d Imprecision: Precise estimates for sensitivity and specificity. 

e Publication bias: Not applicable (the evidence for publication bias in studies of diagnostic test accuracy is very limited).

 

Question: What is the accuracy of symptomatic screening and/or chest x-ray to exclude TB disease in contacts of people with pulmonary TB without HIV in high TB incidence countries?

Index test: Any symptom| Reference test: Sputum culture and/or smear 
Place of testing: Triage 
Test–treatment pathway: Symptom positive ➞ confirmatory test (mycobacterial culture or GeneXpert) ➞ anti-TB chemotherapy (6–9 months’ antibiotics)
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From references 38–48 

a Limitations in study design (see QUADAS-2): High risk of selection bias in one study (38) and unclear risk of bias for the reference standard in two studies. In 9 of the 11 studies, less than half the participants received the reference standard; accuracy was calculated under the assumption that those who did not receive the reference standard were culture- and/or smear-negative (no active TB). 

b Indirectness (see QUADAS-2): no major concern for applicability. 

c Inconsistency: moderate heterogeneity for sensitivity and significant heterogeneity for specificity (based on visual inspection of 95% CIs); downgrading on specificity. 

d Imprecision: precise estimates for sensitivity and imprecise estimate for specificity. 

e Publication bias: not applicable (the evidence for assessing publication bias in studies of diagnostic test accuracy is very limited)

 

PICO 4: Could interferon-γ release assays be used as an alternative to tuberculin skin tests to identify individuals most at risk of progression from TB infection to TB disease in high TB incidence settings?

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Assessment

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Summary of judgements

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Conclusions

Could interferon-γ release assays be used as an alternative to tuberculin skin tests to identify individuals most at risk of progression from TB infection to TB disease in high TB incidence settings?

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GRADE table: Studies that included head-to-head evaluations of the TST and IGRA (N=5)

Review question: Among people at high risk of TB infection who are not treated with tuberculosis preventive therapy, which test (e.g. TST or IGRA) when positive, can best identify individuals most at risk of progression?

Systematic review outcome: The predictive utility of the TST vs. the commercial IGRAs for progression to active tuberculosis
Patients/population: Longitudinal studies of adults and children without active TB at baseline not given preventive therapy
Setting: Community cohorts, individuals attending outpatient clinics (e.g. HIV-positive people), individuals participating in RCTs, household contacts; all in high-incidence countries
Index test: TSR (RT23 purified protein derivative or purified protein derivative-S) and/or commercial blood-based IGRAs (QFT-GIT or T.SPOT.-TB)
Importance: Longitudinal studies on the predictive value of a positive IGRA in TB high-incidence countries (≥ 100/100 000) are still emerging. It is important to determine whether IGRA can be used as a replacement for the widely used TST.
Reference standard: All diagnoses of incident active TB (microbiologically confirmed or not)
Studies: Any longitudinal study design (e.g. prospective or retrospective cohort) in TB high-incidence countries, regardless of immunological status (e.g. HIV-infected or not) or BCG status. Average follow-up should be for at least 1 year but can be either active or passive.
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*Absolute risk: estimated by applying the RR estimate to the risk in the test negatives.

Notes to the GRADE summary table
Overall quality: 
One point was removed from all the studies because none were RCTs. The lowest quality score achievable is 1 out of 4; no minus scores are given.
Quality assessment: Based on the relative effect measure (RR or IRR) for both TST and IGRA. Studies not marked down if estimates for both tests scored high on a specific GRADE quality item.
Other study quality considerations: Newcastle–Ottawa scale quality items were considered when assessing the risk of bias. One point is removed if there is at least one concern.

 

A1: Risk of bias is possible, including selection bias, incorporation bias, ascertainment bias and publication bias. Methods for ascertaining TB included microbiological methods, but not all incident TB cases were confirmed definitively by culture. Publication bias not formally assessed but expected to be likely. Several large prospective studies are under way or unpublished, and their results were not included in this analysis; however, additional results are not expected to change the overall conclusions of this review.
A2: Serious unexplained inconsistency of RR estimate for TST. Points removed for serious inconsistency in either estimate.
A3: Although few studies were included, they involved a range of populations, including adults and children, immunocompromised people and TB contacts, and provided direct evidence for these groups.
A4: Serious imprecision of RR estimate for TST. Lower limit of 95% CI indicates lack of predictivity. Points removed if serious imprecision was identified in either estimate.

 

B1: Risk of bias is possible, including selection bias, incorporation bias, ascertainment bias and publication bias. Incorporation bias could not be ruled out for the cohort of antepartum and postpartum women, because relevant information was not available; moreover, there was concern about selection. The reference standards used in the ART cohort study did not include index tests, and the assessors were not blinded to baseline TST results in patient records. Methods for ascertaining TB included microbiological methods, but not all incident TB cases were definitively diagnosed. Publication bias was not formally assessed but is expected to be likely. Several large prospective studies are under way or are unpublished, and their results were not included in this analysis; however, additional results are not expected to change the overall conclusions of this review.
B2: Serious unexplained inconsistency of RR estimates for both TST and IGRA.
B3: This pooled estimate is based on only two studies: one on HIV-infected people on ART with a median CD4+ of approximately 250, and one on HIV-infected antepartum and postpartum women. No direct evidence for treatment of naive patients or HIV-infected patients with high CD4 counts or other sub-populations of HIV-infected individuals (e.g. children).
B4: Very serious imprecision of RR estimates for both TST and IGRA. The 95% CIs are wide and indicate both significant predictive performance and lack of predictivity. The studies had few events.

 

C1: Risk of bias is possible, including selection bias, incorporation bias (could not be assessed because of lack of information) and publication bias. Publication bias was not formally assessed but was expected to be likely. Several large prospective studies are under way or are unpublished, and their results were not included in this analysis; however, additional results are not expected to change the overall conclusions of this review.
C2: Inconsistency not assessed.
C3: This single study comprised household case contacts in a high-incidence country. No direct evidence for other subpopulations of case contacts.
C4: TST effect estimates seriously imprecise. Lower limit of 95% CI indicates lack of predictivity.

 

D1: Risk of bias is possible, including selection bias, ascertainment bias (microbiological tests not used to diagnose TB), incorporation bias and publication bias. Publication bias was not formally assessed but was expected to be likely. Several large prospective studies are under way or are unpublished, and their results were not included in this analysis; however, additional results are not expected to change the overall conclusions of this review.
D2: Inconsistency not assessed.
D3: This single study comprised health-care workers at a primary health-care clinic. No direct evidence for other subpopulations of health-care workers or all health-care settings.
D4: IGRA and TST effect estimates very seriously imprecise; 95% CIs are wide and indicate both significant predictive performance and lack of predictivity. 
 
E1: Risk of bias is possible, including selection bias, ascertainment bias (inclusion of index tests in methods for ascertaining incident TB) and publication bias. Publication bias was not formally assessed but is expected to be likely. Several large prospective studies are under way or are unpublished, and their results were not included in this analysis; however, additional results are not expected to change the overall conclusions of this review. 
E2: Inconsistency not assessed. 
E3: This single study comprised adolescents in a high-incidence setting. No direct evidence for other subpopulations of children or adolescents. 
E4: No serious imprecision: few events with large sample size.

 

PICO 5: Should 3-month daily rifampicin plus isoniazid (3RH) be offered as a preventive treatment option for children and adolescents <15 years of age as an alternative to 6 or 9 months isoniazid (INH) monotherapy in high TB incidence countries?

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Assessment

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Summary of judgements

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Conclusions 

Should 3-month daily rifampicin/isoniazid (3RH) be offered as preventive treatment option for children and adolescents < 15 years of age as an alternative to 6 or 9 months of isoniazid monotherapy in high TB incidence countries?

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GRADE table 

Question: Should 3-month daily rifampicin/isoniazid (3RH) be offered as preventive treatment option for children and adolescents < 15 years of age as an alternative to 6 or 9 months’ isoniazid monotherapy in high TB incidence countries?

Overall quality: low

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From references 59–61 

a Although there was a risk of selection bias, the characteristics of the two groups were similar. Patients with poor compliance were not included in the analysis of treatment outcomes. Downgraded by one level. 

b There was no clinical disease. The outcome reported was new radiography findings suggestive of possible active disease. No comparison with 6H. Downgraded by one level. 

c High risk of detection bias because of lack of blinding. The RH group included participants enrolled during the second period, whose characteristics were different; they were not randomized between the RH group and the 9H group. Downgraded by two levels. 

d No comparison with 6H. Downgraded by one level. 

e Risk of bias because of non-comparability of the two groups. Downgraded by one level. 

f Low event rate and wide 95% CI. Downgraded by one level. 

g Lack of blinding. Medication adherence test performed at home by parents. Although there was a risk of selection bias, the characteristics of the two groups were similar. Downgraded by one level. 

h Wide 95% CI. Downgraded by one level. 

i Adherence rates reported; compliance considered poor if no medication was detected in urine strips, if patients did not return for follow-up visits or if they were lost to follow-up. Poor compliance was considered non-completion in the analysis.

 

PICO 6: In people of all ages at risk of TB disease, does a 4-month daily rifampicin regimen safely prevent TB disease as compared with other recommended TPT regimens?

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Assessment

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Summary of judgements

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Type of recommendation

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Conclusions

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PICO 7: In people of all ages at risk of TB disease, does a 1-month daily rifapentine plus isoniazid regimen safely prevent TB disease compared to other recommended TPT regimens?

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Assessment

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Summary of judgements

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Type of recommendation

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Recommendation

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PICO 8: Should 3-month weekly rifapentine and isoniazid be offered as an alternative regimen to isoniazid monotherapy for treatment of TB infection in high TB incidence countries?

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Assessment

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Summary of judgements

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Conclusions

Should 3-month weekly rifapentine and isoniazid be offered as an alternative regimen to isoniazid monotherapy for treatment of TB infection in high TB incidence countries?

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GRADE tables 

Question: Should a 3-month regimen of weekly rifapentine plus isoniazid be offered as an alternative regimen to daily isoniazid monotherapy for treatment of TB infection in high TB incidence countries?

Population: Adults with HIV 
Comparison: 6 or 9 months of isoniazid monotherapy

Overall quality: high

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From references 72 and 73 

a Although one of the trials was conducted in low TB incidence countries, this is unlikely to affect the relative effect of RPT/isoniazid compared with isoniazid monotherapy. Not downgraded. 

b 95% CIs of both relative and absolute effect indicate appreciable benefit and harm with 3HP. 

c Both trials were open-label, which may have introduced bias in ascertainment of adverse events. 

d Although the trials were open-label, this is unlikely to affect detection of hepatotoxicity, which is usually done by objective measurement (i.e. blood tests). Not downgraded. 

e Very low event rates. Upper limit of 95% CIs of both relative and absolute effect include appreciable harm with 3HP. Downgraded by two levels.

 

Question: Should a 3-month regimen of weekly rifapentine plus isoniazid be offered as an alternative regimen to daily isoniazid monotherapy for treatment of TB infection in high TB incidence countries?

Population: Adults with HIV 
Comparison: Continuous isoniazid monotherapy 
Overall quality: moderate
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From reference 72 

a 95% CIs of both relative and absolute effect indicate appreciable benefit and harm with 3HP. 

b The trial was open-label, which may have introduced bias in ascertainment of adverse events. 

c Although the trial was open-label, this is unlikely to affect detection of hepatotoxicity, which is usually done by objective measurement (i.e. blood tests). Not downgraded. 

d Very low event rates. The upper limits of 95% CIs of both relative and absolute effect indicate appreciable harm with 3-month weekly RPT and isoniazid. Downgraded by two levels.

 

Question: Should a 3-month regimen of weekly rifapentine plus isoniazid be offered as an alternative regimen to daily isoniazid monotherapy for treatment of TB infection in high TB incidence countries? 

Population: Adults without HIV 
Comparison: 6 or 9 months of isoniazid monotherapy 

Overall quality: moderate

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From reference 74 

a No study provided a comparison with 6 months of isoniazid. The study included 2.7% HIV-positive participants. Although the trial was conducted in low TB incidence countries, this is unlikely to affect the effect of RPT/isoniazid as compared with isoniazid monotherapy. Downgraded by one level. 

b Although the 95% CI of the RR is wide, there were few events, and the CI of the absolute effect is narrow. The result also met pre-stated non-inferiority margin. Not downgraded. 

c Although the 95% CI of the RR is wide, there were few events, and the CI of the absolute effect is narrow. Not downgraded. 

d The open-label design of the trial may have introduced ascertainment bias. Downgraded by one level. 

e Although the trial was open-label, this is unlikely to affect detection of hepatotoxicity, which is usually done by objective measurement (i.e. blood tests). Not downgraded

 

Question: Should a 3-month regimen of weekly rifapentine plus isoniazid be offered as an alternative regimen to daily isoniazid monotherapy for treatment of TB infection in high TB incidence countries?

Population: Children and adolescents 
Comparison: 6 or 9 months’ isoniazid

Overall quality: moderate

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From reference 75 

a No study provided a comparison with 6 months of isoniazid. Although the trial was conducted in low TB incidence countries, this is unlikely to affect the relative effect of RPT/isoniazid as compared with isoniazid monotherapy. Downgraded by one level. 

b Although the 95% CI of the RR is wide, there were few events, and the CI of the absolute effect is narrow. The result also met pre-stated non-inferiority margin. Not downgraded. 

c Although the 95% CI of the RR is wide, there were few events, and the CI of the absolute effect is narrow. Not downgraded. 

d The open-label design of the trial may have introduced ascertainment bias. 

e Although the trial was open-label, this is unlikely to affect detection of hepatotoxicity, which is usually done by objective measurement (i.e. blood tests). Not downgraded.

 

PICO 9: In pregnant and postpartum women, is isoniazid preventive treatment for TB as safe as other preventive treatment regimens?

The Guideline Development Group noted the lack of evidence and therefore decided not to update the existing recommendation. There is therefore no Evidence to Decision table.

 

PICO 10: Should 6 months of levofloxacin compared to other regimen or no TPT be recommended for people in contact with MDR/RR-TB?

Should 6 months of levofloxacin vs. other regimen or no TPT be used for people in contact with MDR/RR-TB?

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Assessment

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Summary of judgements

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Conclusions

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References

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